Transdermal delivery system

ABSTRACT

An improved transdermal delivery system (TDS) comprises a self-adhesive matrix comprising a solid or semi-solid semi-permeable polymer which contains an amine-functional drug in its free base form as a multitude of microreservoirs within the matrix. The self-adhesive matrix is highly permeable to the free base of the amine-functional drug and is impermeable to the protonated form of the amine-functional drug.

This application claims benefit of U.S. Provisional Patent ApplicationNo. 60/451,715 filed Mar. 5, 2003, the entire contents of which arehereby incorporated by reference in their entirety.

This application contains subject matter that is related to U.S. patentapplication Ser. No. 10/623,864 filed on Jul. 22, 2003.

FIELD OF INVENTION

The present invention relates to an improved transdermal delivery systemfor amine functional drugs. Moreover, the invention relates to a methodof treatment using the transdermal delivery system.

TECHNICAL BACKGROUND

To date, various transdermal delivery systems (TDS) for theadministration of amine functional drugs, such as rotigotine and manyothers, have been described. WO 94/07468 discloses a TDS containingrotigotine hydrochloride as active substance in a two-phase matrix,which is essentially formed by a hydrophobic polymer material as thecontinuous phase and a disperse hydrophilic phase contained therein andmainly containing the drug and hydrated silica. The silica is said toenhance the maximum possible loading of the TDS with the hydrophilicsalt. Moreover, the formulation of WO 94/07468 usually containsadditional hydrophobic solvents, permeation promoting substances,dispersing agents and, in particular, an emulsifier which is required toemulsify the aqueous solution of the active component in the lipophilicpolymer phase. A TDS prepared by using such a system has been tested inhealthy subjects and Parkinson's patients. However, no satisfactory drugplasma levels were achieved.

Various further TDSs have been described in WO 99/49852.

In the TDS according to WO 94/07468 and many related applications,passive diffusion membranes were used.

However, as the skin is to be seen as a very efficient barrier for mostdrug candidates, such type of membrane controlled systems are more orless limited in practice to transdermal delivery of active substancesthat reveal a very high skin permeability. Additionally, specialrequirements on drug release kinetics have to be met like contactdelivery over several days.

An object of the present invention is to control (i.e. tocanalise/manoeuvre) the transport of a drug substance towards and acrossthe skin from a drug reservoir, thereby enhancing the flux of the drugsubstance across the TDS/skin interface.

A further object and aspect of the present invention is to provide asuitable composition and manufacturing methods of polymer matrices inTDS which lead to an enhanced delivery of weakly basic amines to andacross the skin by

-   -   (i) preventing back diffusion of the drug portion which is        ionized in the skin according to its pKa value from the skin        tissue into the TDS,    -   (ii) offering continuous delivery of the active compound across        the stratum corneum not only via the common more lipophilic        route (e.g. intercellular) but also through hydrophilic pores        (e.g. eccrine sweat glands).

SUMMARY OF THE INVENTION

There is now provided a TDS comprising a backing layer inert to thecomponents of the matrix, a self-adhesive matrix containing an aminefunctional drug, and a protective foil or sheet to be removed prior touse,

characterized in that

the self-adhesive matrix comprises a solid or semi-solid semi-adhesivepolymer

-   (1) wherein an amine functional drug in its free base form is    incorporated,-   (2) which comprises a multitude of microreservoirs within the    matrix, said microreservoirs containing the amine functional drug    and optionally a crystallization inhibitor,-   (3) which is permeable to the free base of the amine functional    drug,-   (4) which is substantially impermeable to the protonated form of the    amine functional drug,-   (5) wherein the maximum diameter of the microreservoirs is less than    the thickness of the matrix.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of the protonation of the drug in thesemi-permeable matrix on the drug absorption.

FIG. 2 shows the impact of the size distribution of the microreservoirsin the semi-permeable matrix on the drug absorption.

FIG. 3 shows the effect of reducing the amount of the protonated form ofthe drug in the semi-permeable matrix and reducing the size of themicroreservoirs on the drug absorption.

FIG. 4 shows a microscope image of a conventional TDS.

FIG. 5 shows a microscope image of the TDS according to the invention.

FIG. 6 shows the effect of reducing the amount of the protonated form ofthe drug in the semi-permeable matrix and reducing the size of themicroreservoirs on the in vitro skin permeation of the drug.

FIG. 7 shows a comparison of the in vitro skin permeation of the drugfor the TDS of the, invention and an acrylate-based TDS.

DESCRIPTION OF THE INVENTION

The present invention provides a TDS for amine functional drugsproviding a high steady state flux rate of the amine functional drugover the TDS/skin interface.

Surprisingly, it was found that drug release properties of a TDS havinga silicone-type adhesive matrix containing an amine functional drug canbe significantly enhanced by

-   (1) minimizing the amount of the amine functional drug which is    present in the protonated form (salt form);-   (2) incorporating the amine functional drug in a multitude of    microreservoirs within the self-adhesive matrix consisting of a    solid or semi-solid semi-permeable polymer.

The impact of above described measures on drug release characteristicsof rotigotine in vivo is illustrated in FIGS. 1, 2 and 3. The relativedrug absorption in vivo was highest for the sample according to theinvention; increase of the size of the microreservoirs and/or the amountof drug salt residues in the TDS led to slower initial drug release.

Based on the above findings, the present invention was accomplished.

When using the TDS, according to the present invention, a high transferof the amine functional drug from the silicone matrix into the outermostskin layer can be achieved. Consequently, plasma values of the aminefunctional drug are sufficient to allow for a reasonable expectationthat an efficient treatment with these drugs with fewer side effects canbe provided.

It should be understood that the term “treatment” in the context of thisapplication is meant to designate a treatment or an alleviation of thesymptoms of the diseases that can be treated with the amine functionaldrugs useful in this invention. The treatment may be of a therapeutic orprophylactic nature.

In a preferred embodiment the amine functional drug incorporated in theTDS of the present invention has an octanol/water partitioningcoefficient log P>_(—)2.8 at pH 7.4. In another preferred embodiment theamine functional drug has a pKa of 7.4 to 8.4. In an especiallypreferred embodiment the amine functional drug has an octanol/waterpartitioning coefficient log P>_(—)2.8 at pH 7.4 and a pKa of 7.4 to8.4. The pKa-value can be measured by standard methods. A particularlypreferred method is potentiometric titration of aqueous solutions(without addition of organic cosolvents) at room temperature. Theoctanol/water partitioning coefficients (octan-l-of/water partitioningcoefficients) are determined at pH 7.4, 37° C. and an ionic strength of0.15 in an appropriate buffer solution according to the method describedby E. Miyamoto et al. (E. Miyamoto et al. “Physico-chemical Propertiesof Oxybutynin” Analyst (1994), 119, 1489-1492).

Particularly preferred amine functional drugs are dopamine D2 agonists,which are useful for example in the treatment of Parkinson's disease.Especially preferred dopamine D2 receptor agonists are aminotetralinecompounds, such as5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]amino]-1-naphthalenol(INN: rotigotine).

Other examples for particularly preferred amine functional drugs areN-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide (INN: fentanyl)which is useful in the treatment of pain and anticholinergic drugsexerting an antispasmodic effect on smooth muscles and inhibiting themuscarinic action of acetylcholin on smooth muscles. Examples of suchanticholinergic drugs which are useful in the present invention are4-diethylamino-2-butynyl phenylcyclohexyl-glycolate (INN: oxybutynine)and 2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate (INN: fesoterodine). Oxybutynine and fesoterodine are usefulin the treatment of urinary incontinence.

It will be understood by a person skilled in the art that the aminefunctional drugs, such as rotigotine, fentanyl, oxybutynine andfesoterodine, may all exist in various isomeric forms. It has to beunderstood that in this case the amine functional drug may be any singleisomer or a mixture of different isomers. If the amine functional groupcontains asymmetric carbon atoms, any single enantiomer or a mixture ofenantiomers may be used. Rotigotine, fentanyl oxybutynine andfesoterodine all contain one asymmetric carbon atom. Hence, the S- orR-enantiomer or the racemate or any other enantiomer mixture of thesecompounds may be used as the amine functional drug.

At least a part of the amine functional drug is contained in a multitudeof microreservoirs distributed within the self-adhesive matrix of theTDS according to the invention. This does not exclude and will normallyeven imply that a certain fraction of the amine functional drug isdissolved in the solid or semi-solid semi-permeable polymer of thematrix at its saturation concentration.

Within this specification “microreservoirs” are meant to be understoodas particulate, spatially and functionally separate compartmentsconsisting of pure drug or a mixture of drug and crystallizationinhibitor, which are dispersed in the self-adhesive (polymer) matrix.Preferably the self-adhesive matrix contains 10³ to 10⁹ microreservoirsper cm² of its surface, particularly preferred are 10⁶ to 10⁹microreservoirs per cm².

The amine functional drug is incorporated in the self-adhesive matrix inits free base form. This does not totally exclude the presence of someresidual salt form of the amine functional drug in the final TDS.However, the salt form of the amine functional drug should be containedin the self-adhesive matrix of the final TDS in an amount of preferablyless than 5%, more preferably less than 2%, particularly less than 1%(w/w).

If the amine functional drug is present in the self-adhesive matrix inits protonated (salt) form, it will not be released by the self-adhesivematrix. Thus, the amount of the salt form of the amine functional drugcan be determined by performing a drug dissolution test according to thePaddle over Disk method as described in the United States Pharmacopeia(United States Pharmacopeia/New Formulary (USP25/NF20), Chapter 724“Drug Release”, United States Pharmacopeial Convention, Inc., Rockville,Md. 20852, U.S.A. (2002)), using the following conditions: dissolutionmedium: 900 ml phosphate buffer pH 4.5; temperature adjusted to 32±0.5°C.; paddle rotation speed: 50 rpm; sampling times: 0.5, 1, 2 and 3 h,respectively. The increase in the eluted drug concentration can be usedto calculate the amount of unprotonated drug in the matrix.

The amount of the salt form of the amine functional drug may be reducede.g. by reducing the water content of the mass containing the drug andorganic solvent(s). In a particularly preferred embodiment of theinvention the water content is reduced during manufacture to preferablyless than 0.4% (w/w), more preferably less than 0.1%, of the mass.

A further step, which may be taken for reducing the amount of the saltform of the amine functional drug, is isolating the free base form ofthe amine functional drug in solid form prior to the preparation of theTDS. If the free base of the amine functional drug is produced in situduring the manufacture of the TDS by neutralizing an acid addition salt,a certain residue of the ionized drug form will remain in the polymermatrix (usually >5% (w/w) and up to approximately 10%). Therefore, suchin situ preparation of the free base form will generally not be suitablefor practising the present invention.

The maximum diameter of the microreservoirs is less than the thicknessof the matrix, preferably up to 70% of the thickness of the matrix,particularly preferably 5 to 60% of the thickness of the matrix. For anexemplary thickness of the matrix of 50 μm this corresponds to a maximumdiameter of the microreservoirs in the range of preferably up to 35 μm.The term “maximum diameter” is meant to be understood as the diameter ofthe microreservoirs in one dimension (x-, y-, or z-dimension), which isthe largest. It is clear to the skilled person that in case of sphericaldiameters the maximum diameter corresponds to the microreservoir'sdiameter. However, in the case of microreservoirs, which are not shapedin the form of spheres—i.e. of different geometric forms—, the x-, y-and z-dimensions may vary greatly.

As the maximum diameter of the microreservoirs in the direction of thecross-section of the matrix, i.e. between the release surface and thebacking layer, is less than the thickness of the matrix, direct contactbetween the skin and the basic microreservoirs containing theamine-functional drug is avoided, if not at all prevented. Owing to theslightly acidic pH of the skin, direct contact between the skin and themicroreservoirs in the matrix leads to protonation of theamine-functional drug, thereby deteriorating the semi-permeability ofthe matrix.

In a particularly preferred embodiment of the invention, the meandiameter of the microreservoirs containing the amine functional drugsdistributed in the matrix is in the range of 1 to 40%, even morepreferably 1 to 20%, of the thickness of the drug-loaded self-adhesivematrix. For an exemplary thickness of the matrix of 50 μm thiscorresponds to a mean diameter of the microreservoirs in the range ofpreferably 0.5 to 20 μm. The term “mean diameter” is defined as the meanvalue of the x,y,z-average diameters of all microreservoirs. The targetparticle size can be adjusted by the solids content and viscosity of thedrug-containing coating mass.

The maximum and mean diameters of the microreservoirs as well as thenumber of microreservoirs per surface area of the self-adhesive matrixcan be determined as follows: The release liner is removed from the TDS,and the free adhesive surface is examined with a light microscope (Leicamicroscope type DM/RBE equipped with a camera type Basler A 113C). Themeasurement is performed by incidental polarized light analysis using amicroscope at 200× magnification. A picture analysis is performed usingthe software Nikon Lucia_Di, Version 4.21, resulting in mean and maximumdiameters for each sample.

The TDS of the present invention is of the “matrix” type. In such matrixtype TDS the drug is dispersed in a polymer layer. The TDS of the matrixtype in their simplest version comprise a one-phase (monolayer) matrix.They consist of a backing layer, a self-adhesive matrix containing theactive agent and a protective foil or sheet, which is removed beforeuse.

Versions that are more complicated comprise multi-layer matrixes,wherein the drug may be contained in one or more non-adhesive polymerlayers. The TDS of the present invention is preferably a one-phase (monolayer) matrix system.

The solid or semi-solid semi-permeable polymer of the self-adhesivematrix has to satisfy the following requirements:

-   1. Sufficient solubility and permeability for the free base form of    the amine functional drug.-   2. Impermeability for the protonated form of the amine functional    drug.

In a particular preferred embodiment of the invention the self-adhesivematrix is free of particles that can absorb salts of the aminefunctional drug on the TDS/skin interface. Examples of particles thatcan absorb salts of the amine functional drug on the TDS/Skin interfaceinclude silica. Such particles that can adsorb salts of the aminefunctional drug may represent diffusion barriers for the free base formof the drug and may result in the formation of channels inducing somepermeability of the self-adhesive matrix for the protonated form of thedrug. Such embodiments are therefore disadvantageous for practising theinvention.

The self-adhesive matrix of the TDS of the present invention comprises asolid or semi-solid semi-permeable polymer. Usually this polymer will bea pressure sensitive adhesive (PSA) or a mixture of such adhesives. Thepressure sensitive adhesive(s) form a matrix in which the activeingredient and the other components of the TDS are incorporated.

The adhesive used in the present invention should preferably bepharmaceutically acceptable in a sense that it is biocompatible,non-sensitising and non-irritating to the skin. Particularlyadvantageous adhesives for use in the present invention should furthermeet the following requirements:

-   1. Retained adhesive and co-adhesive properties in the presence of    moisture or perspiration, under normal temperature variations,-   2. Good compatibility with the amine functional drug, as well as    with the further excipients used in the formulation.

Although different types of pressure sensitive adhesive may be used inthe present invention, it is preferred to use lipophilic adhesiveshaving both a low drug and low water absorption capacity. Particularpreferably, the adhesives have solubility parameters which are lowerthan those of the amine functional drugs. Such preferred pressuresensitive adhesives for use in the TDS of the present invention aresilicone type pressure sensitive adhesives. Especially preferredpressure sensitive adhesives for use in the TDS of the invention are ofthe type forming a soluble polycondensed polydimethylsiloxane(PDMS)/resin network, wherein the hydroxy groups are capped with e.g.trimethylsilyl (TMS) groups. Preferred adhesives of this kind are theBIO-PSA silicone pressure sensitive adhesives manufactured by DowCorning, particularly the Q7-4201 and Q7-4301 qualities. However, othersilicone adhesives may also be used.

In a further and especially preferred aspect, two or more siliconeadhesives are used as the main adhesive components. It can beadvantageous if such a mixture of silicone adhesives comprises a blendof high tack silicone pressure sensitive adhesive comprisingpolysiloxane with a resin and a medium tack silicone type pressuresensitive adhesive comprising polysiloxane with a resin.

Tack has been defined as the property that enables an adhesive to form abond with the surface of another material upon brief contact under lightpressure (see e.g. “Pressure Sensitive Tack of Adhesives Using anInverted Probe Machine”, ASTM D2979-71 (1982); H. F. Hammond in D. Satas“Handbook of Pressure Sensitive Adhesive Technology” (1989), 2^(nd) ed.,Chapter 4, Van Nostrand Reinhold, New York, page 38).

Medium tack of a silicon pressure sensitive adhesive indicates that theimmediate bond to the surface of another material is weaker compared tohigh tack silicon adhesive. The mean resin/polymer ratio is approx.60/40 for medium tack adhesives, whereas it is approx. 55/45 for hightack adhesives. It is known to the skilled person that both tape andTheological properties are significantly influenced by the resin/polymerratio (K. L. Ulman and R. P. Sweet “The Correlation of Tape Propertiesand Rheology” (1998), Information Brochure, Dow Corning Corp., USA).

Such a blend comprising a high and a medium tack silicone type pressuresensitive adhesive comprising polysiloxane with a resin is advantageousin that it provides for the optimum balance between good adhesion andlittle cold flux. Excessive cold flux may result in a too soft patchwhich easily adheres to the package or to patient's garments. Moreover,such a mixture seems to be particularly useful for obtaining higherplasma levels. A mixture of the aforementioned Q7-4201 (medium tack) andQ7-4301 (high tack) proved to be especially useful as a matrix for theTDS according to the present invention.

In a further preferred embodiment, the TDS further includes acrystallization inhibitor. Several surfactants or amphiphilic substancesmay be used as crystallization inhibitors. They should bepharmaceutically acceptable and approved for use in medicaments. Aparticularly preferred example of such a crystallization inhibitor issoluble polyvinylpyrrolidone, which is commercially available, e.g.under the trademark Kollidon® (Bayer AG). Other suitable crystallizationinhibitors include copolymers of polyvinylpyrrolidone and vinyl acetate,polyethyleneglycol, polypropyleneglycol, glycerol and fatty acid estersof glycerol or copolymers of ethylene and vinyl acetate.

The device of the present invention further comprises a backing layer,which is inert to the components of the matrix. This backing layer is afilm being impermeable to the active compounds. Such a film may consistof polyester, polyamide, polyethylene, polypropylene, polyurethane,polyvinyl chloride or a combination of the aforementioned materials.These films may or may not be coated with an aluminium film or withaluminium vapour. The thickness of the backing layer may be between 10and 100 μm, preferably between 15 and 40 μm.

The TDS of the present invention further comprises a protective foil orsheet, which will be removed immediately prior to use, i.e. immediatelybefore the TDS will be brought into contact with the skin. Theprotective foil or sheet may consist of polyester, polyethylene orpolypropylene which may or may not be coated with aluminium film oraluminium vapour or fluoropolymers. Typically the thickness of such aprotective foil or sheet ranges from between 50 and 150 μm. So as tofacilitate removal of the protective foil or sheet when wishing to applythe TDS, the protective foil or sheet may comprise separate protectivefoils or sheets having overlapping edges, similar to the kind used withthe majority of conventional plasters.

In a preferred embodiment of the present invention, the TDS has a basalsurface area of 5 to 50 cm², particularly of 10 to 30 cm². It goeswithout saying that a device having a surface area of, say, 20 cm² ispharmacologically equivalent to and may be exchanged by two 10 cm²devices or four 5 cm² devices having the same drug content per cm².Thus, the surface areas as indicated herein should be understood torefer to the total surface of all devices simultaneously administered toa patient.

Providing and applying one or several TDS according to the invention hasthe pharmacological advantage over oral therapy that the attendingphysician can titrate the optimum dose for the individual patientrelatively quickly and accurately, e.g. by simply increasing the numberor size of devices given to the patient. Thus, the optimum individualdosage can often be determined after a time period of only about 3 weekswith low side effects.

A preferred content of the amine functional drug in the TDS according tothe invention is in the range of 0.1 to 2.0 mg/cm². Still more preferredare 0.20 to 1.0 mg/cm². If a 7 day patch is desired, higher drugcontents will generally be required.

The device used in the present invention is preferably a patch having acontinuous adhesive matrix in at least its center portion containing thedrug. However, transdermal equivalents to such patches are likewisecomprised by the present invention, e.g. an embodiment where the drug isin an inert but non-adhesive matrix in the center portion of the deviceand is surrounded by an adhesive portion along the edges.

The TDS according to the present invention is prepared by amanufacturing process, which comprises preparing a drug loaded adhesive,coating, drying or cooling and lamination to get the bulk product,converting the laminate into patch units via cutting, and packaging.

The invention and the best mode for carrying it out will be explained inmore detail in the following non-limiting examples.

Invention Example 1 Very Low Salt Content, Small Microreservoirs

252.6 g Rotigotine free base are dissolved in 587.8 g ethanol 100% w/wand mixed with 222.2 g ethanolic solution containing 25% w/wpolyvinylpyrrolidone (Kollidon F 90), 0.11% w/w aqueous sodium bisulfitesolution (10% w/w), 0.25% ascorbyl palmitate and 0.62% DL-α-tocopherol.To the homogenous mixture 1692.8 g BIO-PSA Q7 4301 (73% w/w), 1691.6 gBIO-PSA Q7 4201 (73% w/w) and 416.3 g petrol ether are added and allcomponents are stirred for at least 1 hour to get a homogenousdispersion.

For manufacture of the patch matrix, the dispersion is coated onto asuitable release liner (for example Scotchpak 1022) and the solvents arecontinuously removed in a drying oven at temperatures up to 80° C. toget a drug-containing adhesive matrix of 50 g/m² coating weight. Thedried matrix film is laminated with a polyester-type backing foil whichis siliconized on the inner side and aluminium vapor coated on theopposite side.

The individual patches are punched out of the complete laminate and aresealed into pouches under a nitrogen flow. The rotigotine contained inthe matrix was quantitatively released after 3 hours in the drugdissolution test according to the Paddle over Disk method as describedin the USP using the conditions as described above. This resultindicates that the obtained TDS was completely free of rotigotinehydrochloride.

The mean size of the microreservoirs in the TDS was approx. 10 μm withtypical sizes in the range of 5 to 35 μm. A microscope image of theobtained TDS is shown in FIG. 5.

Comparative Example 1 High Salt Content, Small Microreservoirs

2400 g Rotigotine hydrochloride were added to a solution of 272.8 g NaOHin 3488 g ethanol (96%). The resulting mixture was stirred forapproximately 10 minutes. Then 379.2 g of sodium phosphate buffersolution (27.6 g Na₂HPO₄×2H₂O) and 53.2 g Na₂HPO₄×2H₂O in 298.5 g water)was added. Insoluble or precipitated solids were separated from themixture by filtration. The filter was rinsed with 964 g ethanol (96%) toobtain a particle-free ethanolic solution of rotigotine essentially inthe form of the free base.

The rotigotine solution (6150 g) in ethanol (30% w/w) was mixed with 407g ethanol (96%). The resulting solution was mixed with 1738.8 g of anethanolic solution containing 25 wt. % polyvinylpyrrolidone (Kollidone®90F), 0.11 wt. % aqueous sodium bisulfite solution (10 wt. %), 0.25 wt.% ascorbyl palmitate, and 0.62 wt. % DL-alpha-tocopherol untilhomogeneity. To the mixture 13240 g of an amine resistant high tacksilicone adhesive (BIO-PSA® Q7-4301 mfd. by Dow Corning) (73 wt. %solution in heptane), 13420 g of an amine resistant medium tack siliconeadhesive (BIO-PSA® Q7-4201 mfd. by Dow Corning) (72 wt. % solution inheptane), and 3073 g petrol ether were added, and all components werestirred until a homogenous dispersion was obtained.

The dispersion was coated onto a suitable polyester release liner(SCOTCHPAK® 1022) with a suitable doctor knife and the solvents werecontinuously removed in a drying oven at temperatures up to 80° C. forabout 30 minutes to obtain a drug containing adhesive matrix of 50 g/m²coating weight. The dried matrix film was laminated with apolyester-type backing foil (SCOTCHPAK® 1109). The individual patcheswere punched out of the complete laminate in the desired sizes (e.g. 10cm², 20 cm², 30 cm²) and sealed into pouches under the flow of nitrogen.

Only approx. 95% of the rotigotine contained in the matrix were releasedafter 3 hours in the drug dissolution test according to the Paddle overDisk method as described in the USP using the conditions as describedabove. Thus, the obtained TDS contained approx. 5% (w/w) of protonatedrotigotine.

The mean size of the microreservoirs in the TDS was approx. 15 μm withtypical sizes in the range of 10 to 20 μm.

Comparative Example 2 High Salt Content, Large Microreservoirs

150 g Rotigotine hydrochloride were added to a solution of 17.05 g NaOHin 218 g ethanol (96%). The resulting mixture was stirred forapproximately 10 minutes. Then 23.7 g of sodium phosphate buffersolution (8.35 g Na₂HPO₄×2H₂O and 16.07 g NaH₂PO₄×2H₂O in 90.3 g water)was added. Insoluble or precipitated solids were separated from themixture by filtration. The filter was rinsed with 60.4 g ethanol (96%)to obtain a particle-free ethanolic solution of rotigotine essentiallyin the form of the free base.

The rotigotine solution (346.4 g) in ethanol (35% w/w) was mixed with36.2 g ethanol (96%). The resulting solution was mixed with 109 g of anethanolic solution containing 25 wt % polyvinylpyrrolidone (KOLLIDON®90F), 0.077 wt % aqueous sodium bisulfite solution (10 wt %), 0.25 wt %ascorbyl palmitate, and 0.63 wt % DL-alpha-tocopherol until homogenous.To the mixture, 817.2 g of an amine resistant high tack siliconeadhesive (BIO-PSA® Q7-4301 mfd. by Dow Corning) (74 wt % solution inheptane), 851.8 g of an amine resistant medium tack silicone adhesive(BIO-PSA® Q7-4201 mfd. by Dow Corning) (71 wt % solution in heptane),and 205.8 g petrol ether (heptane) were added, and all components werestirred until a homogenous dispersion was obtained.

The dispersion was coated onto a suitable polyester release liner(SCOTCHPAK® 1022) with a suitable doctor knife and the solvents werecontinuously removed in a drying oven at temperatures up to 80° C. forabout 30 min to obtain a drug-containing adhesive matrix of 50 g/m²coating weight. The dried matrix film was laminated with apolyester-type backing foil (SCOTCHPAK® 1109). The individual patcheswere punched out of the complete laminate in the desired sizes (e.g. 10cm², 20 cm², 30 cm²) and sealed into pouches under the flow of nitrogen.

Owing to the large microreservoirs in the TDS' matrix, it was possibleto dissolve the rotigotine salts by direct contact with the dissolutionmedium. Thus, it was not possible to determine the amount of theprotonated form of rotigotine. This indicates that the maximum diameterof the microreservoirs was larger than the thickness of the matrix.

The mean size of the microreservoirs in the TDS was approx. 50 μm withtypical sizes in the range of 20 to 90 μm. A microscope image of theobtained TDS is shown in FIG. 4.

As rotigotine was released from rotigotine hydrochloride in a mannersimilar to Comparative Example 1, one may conclude that the obtained TDSalso contained 5% (w/w) of rotigotine in its protonated form.

Comparative Example 3 Acrylate-Type Formulation

A mixture of 50.0 g rotigotine hydrochloride and 28.6 g sodiumtrisilicate in 95 g methyl ethyl ketone was stirred at room temperaturefor 48 hours. Subsequently, 17.9 g oleic alcohol, 128.6 g of anacrylic-type adhesive solution (51.4% w/w in ethyl acetate; trade name:Durotak® 387-2287 from NATIONAL STARCH & CHEMICAL), 33.0 g of EUDRAGIT®E100 (from ROEHM PHARMA) (50% w/w solution in ethyl acetate) and 45.0 gethyl acetate were added, and the mass was homogenised mechanically.

The dispersion was coated onto a suitably siliconised process liner(Hostaphan® RN 100), and the solvents were evaporated at 50° C. over 30minutes, thereby obtaining a matrix weight of 60 g/m². The dry film waslaminated with a suitable polyester foil (Hostaphan® RN 15). Individualpatches having a desired size of (e.g. 20 cm²) were punched out of theresulting laminate and sealed into pouches under the flow of nitrogen.

Example 2 In Vivo Drug Absorption Test

In order to monitor the absorption of the amine functional drug by thehuman skin the following experiment was carried out. The test wasperformed with the TDS obtained in Example 1 as well as in ComparativeExamples 1 and 2.

The plasma concentration time profile at different test times wasdetermined in pharmacokinetic studies involving (A) 14 healthy malepersons (TDS of Comparative Examples 2 and 3) or (B) 30 healthy malepersons (TDS of Example 1 and Comparative Example 1), respectively. Thestudies were conducted following an open single-dose randomised (B)two-way or (A) three-way cross-over design.

Individual concentrations of rotigotine were determined by means ofliquid chromatography and mass spectroscopy. The lower limit ofquantification (LOQ) was 10 pg/ml.

The drug absorption was calculated from the plasma concentration dataaccording to the Wagner-Nelson method (Malcom Rowland, Thomas N. Tozer(Eds.) “Estimation of Adsorption Kinetics from Plasma ConcentrationData” in Clinical Pharmacokinetics, pp 480-483, Williams & Wilkins,1995), 100%=absorption rate after 48 hours; patch application time was24 hours.

A comparison of the flux across human skin for the different TDS testedis shown in FIGS. 1, 2 and 3.

In FIG. 1 the rotigotine absorption for the sample obtained in Example 1containing no salt (◯) is compared to the sample obtained in ComparativeExample 1 containing approx. 5% (w/w) of rotigotine hydrochloride (●).The comparison in FIG. 1 clearly shows that the drug absorption afterpatch application depends on the residual salt content in thesemi-permeable matrix and is significantly improved by reducing theamount of the protonated form of the amine-functional drug present inthe matrix.

FIG. 2 shows the impact of the size distribution of the microreservoirsdistributed in the semi-permeable matrix by comparing the sampleobtained in Comparative Example 1 having a mean microreservoir size ofapprox. 15 μm and typical sizes between 10 and 20 μm (●) with the sampleobtained in Comparative Example 2 having a mean microreservoir size ofapprox. 50 μm and typical sizes between 20 and 90 μm (▴). From thiscomparison it can be deduced that reducing the size of the matrixreservoirs significantly increases the flux across the human skin.

A comparison between the TDS of Example 1 (◯) and Comparative Example 2(▴) is shown in FIG. 3. This comparison clearly indicates that the fluxacross human skin is significantly enhanced by reducing the salt contentand decreasing the size of the microreservoirs.

Example 3 In Vitro Diffusion Experiment with Transdermal Drug DeliverySystems

The test was performed with a sandwich of consecutively a supportiveseparator membrane, skin and the TDS. Active substance that has diffusedfrom the TDS through the skin and/or membrane dissolves in an acceptorliquid that continuously passes directly underneath the membrane; theacceptor liquid was collected in tubes in a fraction collector; and thefractions were analysed for their content of rotigotine. The flux ofactive substance through skin was calculated by correcting for theinfluence of the separator membrane.

The diffusion cell described in Tanojo et al. (Tanojo et al. “New designof a flow through permeation cell for in vitro permeation studies acrossbiological membranes” Journal of Controlled Release (1997), 45, 41-47)was used in order to conduct the experiment.

A flask containing the acceptor liquid and the assembled diffusion cellswere placed in a temperature-controlled water-bath (32.0±0.5° C.). Theacceptor liquid was continuously pumped from the flask through PTFEtubing by a peristaltic pump, passed through the diffusion cells wherethe diffusion takes place and was then transported via PTFE tubing totest tubes that were placed in a fraction collector.

The required number of disks was punched out from the TDS by using acircular knife. Human epidermis, excised to a thickness of 200-300 μmfrom fresh donor skin (storage ≦36 hours at 4° C.) with a dermatome (tobe referred to as skin) was spread out on laboratory film inpetridishes. Using the circular knife the required number of disks waspunched out. A disk of membrane was centred on each cell surface. Theskin disks were spread out on the membrane disks on the cell surfaceswith the aid of forceps. A disk of the TDS is applied to each cell, andthe cells were assembled. The experiment was then conducted in a mannersimilar to the one described in Tanojo et al above.

Afterwards the tubes containing the collected fraction were weighed, andthe contents of each tube were analysed using HPLC.

This experiment was carried out for the TDS of Example 1 as well asComparative Examples 2 and 3.

FIG. 6 shows the in vitro skin permeation profile for the TDS of Example1 (●) compared to the TDS of Comparative Example 2 (◯).

FIG. 7 shows the in vitro skin permeation profile for the TDS of Example1 (●) compared to the acrylate TDS of Comparative Example 3 (◯).

It is clear from the data obtained that the flux across human skin maybe significantly enhanced by controlling the size of the microreservoirsin the TDS while at the same time providing a semi-permeable matrix,which is highly permeable for the free base of the amine functional drugwhile being impermeable for its protonated form.

1. A transdermal delivery system (TDS) comprising a self-adhesive matrixcontaining a self-adhesive polymer and microreservoirs containing anamine-functional drug in free base form selected from the groupconsisting of fentanyl and oxybutynin, wherein the microreservoirs arewithin the self-adhesive matrix and have a maximum diameter less thanthe thickness of the self-adhesive matrix; and wherein the self-adhesivematrix is permeable to the amine-functional drug in free base form, andthe self-adhesive matrix is substantially impermeable to the aminefunctional drug in protonated form.
 2. The TDS of claim 1, wherein themean diameter of the microreservoirs is in the range of 0.5 to 20 μm. 3.The TDS of claim 1, wherein the self-adhesive matrix is free of silicaparticles that can absorb salts of the amine functional drug at theTDS/skin interface.
 4. The TDS of claim 1, wherein the self-adhesivematrix comprises a silicone pressure sensitive adhesive.
 5. The TDS ofclaim 1, wherein the self-adhesive matrix comprises two or more siliconepressure sensitive adhesives.
 6. The TDS of claim 5, wherein thesilicone pressure sensitive adhesive is a blend of a high tack siliconepressure sensitive adhesive comprising polysiloxane with a resin and amedium tack silicone pressure sensitive adhesive comprising polysiloxanewith a resin.
 7. The TDS of claim 1, wherein the microreservoirs furthercontain at least one crystallization inhibitor comprising solublepolyvinylpyrrolidone, a copolymer of polyvinylpyrrolidone and vinylacetate, polyethylene glycol, polypropylene glycol, glycerol, a fattyacid ester of glycerol and/or a copolymer of ethylene and vinyl acetate.8. The TDS of claim 7, wherein the at least one crystallizationinhibitor comprises soluble polyvinylpyrrolidone.
 9. The TDS of claim 1,wherein the self-adhesive matrix contains 10³ to 10⁹ microreservoirs percm² of the surface of the matrix.
 10. The TDS of claim 1, wherein themaximum diameter of the microreservoirs is not greater than 35 μm. 11.The TDS of claim 1, further comprising a protective foil or sheet to beremoved prior to use.
 12. The TDS of claim 1, further comprising abacking layer.
 13. The TDS of claim 12, wherein the backing layer isinert to the components of the matrix.
 14. The TDS of claim 1, whereinthe self-adhesive matrix comprises a solid or semisolid semi-permeablepolymer.
 15. The TDS of claim 1, wherein the self-adhesive matrixcontains 10⁶ to 10⁹ microreservoirs per cm² of the surface of thematrix.
 16. The TDS of claim 1, further comprising a backing layer beinginert to the component of the matrix, and a protective foil or sheet tobe removed prior to use, wherein the matrix contains 10³ to 10⁹microreservoirs per cm² of the surface of the matrix, and wherein themaximum diameter of the microreservoirs is less than the thickness ofthe matrix and is not greater than 35 μm.
 17. A transdermal deliverysystem (TDS) comprising a self-adhesive matrix containing aself-adhesive polymer and microreservoirs containing an amine-functionaldrug in free base form selected from the group consisting ofaminotetralin compounds, wherein the microreservoirs are within theself-adhesive matrix and have a maximum diameter less than the thicknessof the self-adhesive matrix; and wherein the self-adhesive matrix ispermeable to the amine-functional drug in free base form, and theself-adhesive matrix is substantially impermeable to the aminefunctional drug in protonated form.